In addition to reducing surface tension in the lung, surfactant proteins SP-A and SP-D have important immunomodulatory functions. For example, both SP-A and SP-D enhance bacterial and viral clearance via modulation of immune cell function. Mice deficient in SP-A or SP-D are generally more susceptible to bacterial and viral infection and subsequent inflammation. Little is known, however, about the role of SP-A or SP-D in mediating the host response to fungal infections, in spite of the increasing prevalence of these infections in the second half of the 20th century. We propose to investigate the role of SP-D in the host response to fungal infections using the model organism Cryptococcus neoformans, an environmental yeast-like pathogen that infects the lung and then disseminates to other organs where it frequently results in life threatening meningoencephalitis in both immunocompetent and immunocompromised hosts. C. neoformans has many advantages as a model system including its importance as a human pathogen, the existence of mutant libraries, its genetic manipulability, and mouse models that closely resemble the human disease. We are focusing on SP-D since our data show that SP-A does not bind nor modulate the host response to C. neoformans. Our preliminary data suggest that, unlike its role in protecting the host against bacterial and viral infections, SP-D enhances host susceptibility to infection with C. neoformans. Specifically, we have found that SP-D binds to C. neoformans, enhances its phagocytosis but decreases killing in vitro. Importantly, SP-D null mice are more resistant to C. neoformans infection than are wild type mice. Therefore, the hypothesis to be tested in this proposal is that C. neoformans subverts the normally protective host defense functions of SP-D. The availability of animal models deficient in SP-D and the existence of well established molecular genetics and immunological tools for the study of C. neoformans pathogenesis provide us with the unique opportunity to study the host-pathogen interaction from the perspective of both the host and the pathogen. Since C. neoformans is a leading cause of morbidity and mortality in immunocompromised patients and since the lung is the primary route of infection, an understanding of the role of SP-D in defense against C. neoformans and lung homeostasis could lead to important new therapeutic interventions. PUBLIC HEALTH RELEVANCE: The proposed studies will contribute to our understanding of the role of lung surfactant in pulmonary host defense against infection. We will focus on a model fungal pathogen, C. neoformans, which is a leading cause of morbidity and mortality in immunocompromised patients, such as those with HIV or undergoing chemotherapy. Since the lung is the primary route of infection, an understanding of the role of surfactant in defense against C. neoformans could lead to important new therapeutic interventions for both C. neoformans and other fungal infections.